PROJECT SUMMARY Pediatric high-grade gliomas are devastating central nervous system (CNS) tumors. In the most malignant form of the disease, glioblastoma multiforme (GBM), over 80% of children will succumb to their disease within 5 years after surgery, radiation therapy (RT) and chemotherapy. Many systemic agents have been tested over the last 40 years without changes in survival. These agents likely failed because they cannot cross the blood- brain-barrier (BBB). For the minority of drugs with CNS penetration, high concentrations and uniform distributions in the brain remain a major efficacy barrier. Attempts at systemic dose escalation are limited by extracranial toxicity. As such, better formulations and drug delivery systems are needed for this disease. Such formulations have been created and tested for adult brain tumors, but their application in the pediatric setting has been lacking. To address this unmet need, we propose a multi-PI investigator approach?led by a bioengineer and an oncology physician/scientist?to develop a novel approach for safe and effective drug delivery in the brain for treating pediatric tumors. Although the BBB limits the effectiveness of chemotherapy in pediatric brain tumors, it is now known that agents can be delivered locally?directly into the brain, beyond the blood-brain barrier. In adults, this is accomplished with a dime-size degradable wafer (Gliadel) that is placed in the tumor resection bed during surgery. Gliadel slowly releases the drug for several weeks after placement. But Gliadel has limitations. Because it relies on diffusion of an agent into the tissue, high levels of drug are achieved only within a few millimeters of the wafer. Areas of tumor infiltration in the surrounding brain may be several centimeters from the wafer, and the drugs likely cannot reach them. Another approach, called convection-enhanced delivery (CED), potentially solves these problems by using fluid flow to carry drug molecules through the brain. CED has been shown to be safe but, so far, CED treatments have not been effective. Part of the problem is that the infusion of agents dissolved in liquid, even by CED, does not provide the necessary duration of exposure. We recognize these limitations and are creating an improved drug formulation/delivery system in which 1) nanoparticles are infused locally into the tumor by CED; 2) the nanoparticles are loaded with DNA repair inhibitors known to chemo- and radio-sensitize gliomas; and 3) the nanoparticles release the inhibitors over a sustained time period, so that the agents are present in tumor cells throughout the course of conformal RT, and even during adjuvant chemotherapy. In this unprecedented triple targeted approach, nanoparticles gain access to targeted regions of the brain, releasing agents that target DNA repair in the tumor, and RT is targeted to the volume of the brain where the tumor cells reside. Given that the nanoparticles are composed of a polymer that is approved by the FDA for human use, this approach has the potential to be rapidly adopted into practice, and it could radically change the way that pediatric GBMs are treated.